CN112920112A - Quinoline series medical intermediate synthesis process - Google Patents
Quinoline series medical intermediate synthesis process Download PDFInfo
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- CN112920112A CN112920112A CN202110228461.4A CN202110228461A CN112920112A CN 112920112 A CN112920112 A CN 112920112A CN 202110228461 A CN202110228461 A CN 202110228461A CN 112920112 A CN112920112 A CN 112920112A
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- Prior art keywords
- solution
- sodium hydroxide
- room temperature
- quinoline series
- reaction
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 11
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title claims abstract 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 14
- 239000012065 filter cake Substances 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims abstract description 5
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000002386 leaching Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 81
- 239000000243 solution Substances 0.000 claims description 31
- 239000007787 solid Substances 0.000 claims description 12
- 239000000543 intermediate Substances 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000012086 standard solution Substances 0.000 claims description 4
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 4
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000012043 crude product Substances 0.000 abstract description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 14
- 150000003248 quinolines Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical group C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- -1 heterocyclic aromatic organic compound Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 231100000817 safety factor Toxicity 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a quinoline series medical intermediate synthesis process, which comprises the following steps: when the room temperature is 20 ℃, dissolving SM in ethanol, adding ethyl acetoacetate, adding anhydrous magnesium sulfate, adding L acetic acid, and finishing the reaction after reacting for 18 hours; step two: cooling the solution to room temperature, filtering, draining a filter cake, leaching with ethanol, and concentrating the filtrate to dryness to obtain a reddish brown liquid; step three: heating the reddish brown liquid obtained in the step two to 70 ℃, pouring 75% sulfuric acid into a 50L reaction kettle, heating to 80 ℃, and slowly dripping SM into the reaction bottle; step four: stirring for 30min after adding, detecting no raw material, dripping 10L water, and treating; step five: the solution is cooled to room temperature and then 10L of water is added, the pH value of the solution is between 7 and 8, the synthesis process of the quinoline series medical intermediate realizes the simplicity and convenience of operation, the first step reaction can directly carry out ring closing operation under the condition of a crude product, the yield is not influenced, and the solvent is simple, cheap and convenient to operate.
Description
Technical Field
The invention relates to a synthesis method of quinoline, in particular to a synthesis process of quinoline series medical intermediates, belonging to the technical field of quinoline synthesis.
Background
Quinoline, also known as benzopyridine and azanaphthalene, is a heterocyclic aromatic organic compound and also a colorless hygroscopic liquid with a strong odor and has the molecular formula of C9H 7N. Exposure of quinoline to light slowly turns pale yellow, further brown. Quinoline is slightly soluble in water, but readily soluble in many organic solvents. Quinoline is an important intermediate in the metallurgical, dye, polymer and agrochemical industries and it can also be used as a disinfectant, preservative and solvent.
The quinoline series products are not produced by a plurality of manufacturers on the market, one of the main problems is that the ring closing process needs very high temperature, in the actual amplification process, safety factors are considered by a plurality of factories, generally, synthesis operation of more than 200 ℃ is not selected, and the conventional solvent is diphenyl ether, biphenyl eutectic and other high boiling point solvents, the ring closing can be realized only by heating the temperature to 250 ℃ in use, partial product decomposition or isomer generation is usually caused due to the overhigh temperature, and the special equipment is needed in the large production process for convenient operation. The product of the ring closing step is dark brown and difficult to purify.
Disclosure of Invention
The invention aims to provide a process for synthesizing quinoline series medical intermediates, which aims to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme: the quinoline series medical intermediate synthesis process comprises the following steps:
the method comprises the following steps: when the room temperature is 20 ℃, dissolving 8kg of SM in 56L of ethanol, adding 8.5kg of ethyl acetoacetate, adding 12.5kg of anhydrous magnesium sulfate, adding 280mL of acetic acid, heating to 80-85 ℃, refluxing, and finishing the reaction after reacting for 18 h;
step two: cooling the solution to room temperature, filtering, draining a filter cake, leaching with ethanol, and concentrating the filtrate to dryness to obtain a reddish brown liquid;
step three: heating the reddish brown liquid obtained in the step two to 70 ℃, pouring 75% sulfuric acid into a 50L reaction kettle, heating to 80 ℃, and slowly dripping 8kgSM into the reaction bottle;
step four: stirring for 30min after adding, detecting no raw material, dripping 10L water, and treating;
step five: cooling the solution to room temperature, adding 10L of water, adding 11.4kg of sodium hydroxide aqueous solution in batches, controlling the temperature to be not more than 40 ℃, after the solution is added, keeping the pH value of the solution between 7 and 8, separating out a large amount of solids, and filtering.
As a preferred technical scheme of the invention, in the fifth step, the filter cake is stirred for 1 hour by 50L of water, filtered, and dried to obtain 5.5kg of filter cake with the yield of 85%.
As a preferable technical scheme of the invention, in the step four, the preparation of the sodium hydroxide solution as the sodium hydroxide standard solution requires firstly weighing 50 g of sodium hydroxide solid, dissolving the sodium hydroxide solid in a small beaker by using a small amount of distilled water, then transferring the sodium hydroxide solution in the beaker to a 56L reaction kettle, and stirring for 1h to prepare the sodium hydroxide solution.
As a preferred technical scheme of the invention, when 8kgSM is added in the third step, the heat release is obvious, and the temperature is controlled not to exceed 110 ℃.
As a preferable technical scheme of the invention, the yield of the red brown liquid obtained by concentrating the filtrate in the second step to be dry is more than 100%.
Compared with the prior art, the invention has the beneficial effects that: the invention relates to a process for synthesizing quinoline series medical intermediates, which realizes low-temperature ring closure of acid catalysis, can perform ring closure at conventional temperature, avoids production risk and reduces energy cost, screens substrates with various structures in the process, determines that the route is a universal scheme, can aim at a plurality of substrates, and realizes simple and convenient operation, the first step reaction can directly perform ring closure operation under the condition of crude products, does not influence yield, has simple and cheap solvent and convenient operation, introduces 75% sulfuric acid solution as a ring closure catalyst, can perform ring closure at the temperature of 80 ℃, and can easily obtain target products and obtain pure products due to poor solubility of the products.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The whole reaction process of the invention is as follows:
the first embodiment is as follows: the invention provides a quinoline series medical intermediate synthesis process, which comprises the following steps: when the room temperature is 20 ℃, dissolving 8kg of SM in 56L of ethanol, adding 8.5kg of ethyl acetoacetate, adding 12.5kg of anhydrous magnesium sulfate, adding 280mL of acetic acid, heating to 80-85 ℃, refluxing, and finishing the reaction after reacting for 18 h;
step two: cooling the solution to room temperature, filtering, draining a filter cake, leaching with ethanol, and concentrating the filtrate to dryness to obtain a reddish brown liquid;
step three: heating the reddish brown liquid obtained in the step two to 70 ℃, pouring 75% sulfuric acid into a 50L reaction kettle, heating to 80 ℃, and slowly dripping 8kgSM into the reaction bottle;
step four: stirring for 30min after adding, detecting no raw material, dripping 10L water, and treating;
step five: cooling the solution to room temperature, adding 10L of water, adding 11.4kg of sodium hydroxide aqueous solution in batches, controlling the temperature to be not more than 40 ℃, after the solution is added, keeping the pH value of the solution between 7 and 8, separating out a large amount of solids, and filtering.
The solution yield was found to be greater than 100%.
Wherein, the filter cake in the fifth step is stirred for 1h by 50L of water, and then filtered, and the filter cake is dried to obtain 5.5kg, and the yield is 85%.
Further, in the step four, the preparation of the sodium hydroxide standard solution by using the sodium hydroxide solution requires firstly weighing 50 g of sodium hydroxide solid, dissolving the sodium hydroxide solid in a small beaker by using a small amount of distilled water, then transferring the sodium hydroxide solution in the beaker to a 56L reaction kettle, and stirring for 1h to prepare the sodium hydroxide solution.
Further, the addition of 8kgSM in step three gave a significant exotherm with the temperature controlled to not exceed 110 ℃.
Example two: the invention provides a quinoline series medical intermediate synthesis process, which comprises the following steps: when the room temperature is 20 ℃, dissolving 7kg of SM in 56L of ethanol, adding 7.5kg of ethyl acetoacetate, adding 11.5kg of anhydrous magnesium sulfate, adding 250mL of acetic acid, heating to 75-85 ℃, refluxing, and finishing the reaction after reacting for 16 h;
step two: cooling the solution to room temperature, filtering, draining a filter cake, leaching with ethanol, and concentrating the filtrate to dryness to obtain a reddish brown liquid;
step three: heating the reddish brown liquid obtained in the step two to 60 ℃, pouring 65% sulfuric acid into a 50L reaction kettle, heating to 70 ℃, and slowly dripping 7kgSM into a reaction bottle;
step four: stirring for 30min after adding, detecting no raw material, dripping 10L water, and treating;
step five: cooling the solution to room temperature, adding 10L of water, adding 11.4kg of sodium hydroxide aqueous solution in batches, controlling the temperature to be not more than 40 ℃, after the solution is added, keeping the pH value of the solution between 7 and 8, separating out a large amount of solids, and filtering.
The solution yield was found to be less than 100%.
Wherein, the filter cake in the fifth step is stirred for 1h by 50L of water, and then filtered, and the filter cake is dried to obtain 4.5kg, and the yield is 75%.
Further, in the step four, the preparation of the sodium hydroxide standard solution by using the sodium hydroxide solution requires firstly weighing 50 g of sodium hydroxide solid, dissolving the sodium hydroxide solid in a small beaker by using a small amount of distilled water, then transferring the sodium hydroxide solution in the beaker to a 56L reaction kettle, and stirring for 1h to prepare the sodium hydroxide solution.
Further, the exotherm was significant with the addition of 7kgSM in step three, and the temperature was controlled not to exceed 110 ℃.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. The quinoline series medical intermediate synthesis process is characterized by comprising the following steps:
the method comprises the following steps: when the room temperature is 20 ℃, dissolving 8kg of SM in 56L of ethanol, adding 8.5kg of ethyl acetoacetate, adding 12.5kg of anhydrous magnesium sulfate, adding 280mL of acetic acid, heating to 80-85 ℃, refluxing, and finishing the reaction after reacting for 18 h;
step two: cooling the solution to room temperature, filtering, draining a filter cake, leaching with ethanol, and concentrating the filtrate to dryness to obtain a reddish brown liquid;
step three: heating the reddish brown liquid obtained in the step two to 70 ℃, pouring 75% sulfuric acid into a 50L reaction kettle, heating to 80 ℃, and slowly dripping 8kgSM into the reaction bottle;
step four: stirring for 30min after adding, detecting no raw material, dripping 10L water, and treating;
step five: cooling the solution to room temperature, adding 10L of water, adding 11.4kg of sodium hydroxide aqueous solution in batches, controlling the temperature to be not more than 40 ℃, after the solution is added, keeping the pH value of the solution between 7 and 8, separating out a large amount of solids, and filtering.
2. The process for synthesizing quinoline series pharmaceutical intermediates according to claim 1, wherein: and in the fifth step, the filter cake is stirred for 1 hour by 50L of water, the filtration is carried out, and the filter cake is dried to obtain 5.5kg, wherein the yield is 85%.
3. The process for synthesizing quinoline series pharmaceutical intermediates according to claim 1, wherein: in the fourth step, 50 g of sodium hydroxide solid is weighed to prepare a sodium hydroxide standard solution, a small amount of distilled water is used for dissolving the sodium hydroxide solid in a small beaker, then the sodium hydroxide solution in the beaker is transferred to a 56L reaction kettle, and the sodium hydroxide solution is prepared by stirring for 1 h.
4. The process for synthesizing quinoline series pharmaceutical intermediates according to claim 1, wherein: when 8kgSM is added in the third step, the heat release is obvious, and the temperature is controlled not to exceed 110 ℃.
5. The process for synthesizing quinoline series pharmaceutical intermediates according to claim 1, wherein: and in the second step, the filtrate is concentrated to be dry to obtain a reddish brown liquid, and the yield of the reddish brown liquid is more than 100%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110228461.4A CN112920112A (en) | 2021-03-02 | 2021-03-02 | Quinoline series medical intermediate synthesis process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110228461.4A CN112920112A (en) | 2021-03-02 | 2021-03-02 | Quinoline series medical intermediate synthesis process |
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| CN112920112A true CN112920112A (en) | 2021-06-08 |
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| CN202110228461.4A Pending CN112920112A (en) | 2021-03-02 | 2021-03-02 | Quinoline series medical intermediate synthesis process |
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- 2021-03-02 CN CN202110228461.4A patent/CN112920112A/en active Pending
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Application publication date: 20210608 |
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